The emerging importance of BCL11A in normal and malignant B-cell development is highlighted by several recent observations. Experiments in the mouse have shown that BCL11A, a zinc-finger transcription factor, is essential for normal B-cell development as well as the survival of the organism. BCL11A also has been implicated in diverse types of B-cell malignancy due to recurrent chromosomal translocation, gene amplification, or retroviral integration. In spite of such progress, the functions of BCL11A during normal B-cell differentiation, as well as its protein expression pattern and its probable transcriptional regulation of downstream target genes, are largely unknown. This project proposes to further our understanding in these three areas by (1) the development of new antibody reagents directed against BCL11A protein isoforms, (2) the identification and validation of target genes using cDNA microarray technology, and (3) conditional gene-targeting of BCL11A in embryonic stem cells. Significant progress has been made in Aims (1) and (2). Our discovery of a novel BCL11A isoform (coupled with the success of Aims (1) and (2)) allows us to test the hypothesis that BCL11A is an integral component of a gene network regulating plasma cell differentiation. Furthermore, this novel isoform may be diagnostic for a common transcriptional profile shared by several lymphomas derived from post-germinal-center B cells, namely, Hodgkin lymphoma, primary effusion lymphoma, and multiple myeloma.